S-[(1 and 2)-Phenyl-2-hydroxyethyl]cysteine-Induced Alterations in Renal Mitochondrial Function in Male Fischer-344 Rats

Previous studies from our laboratory have shown that mitochondrial dysfunction may be an important early event inS-[(1 and 2)-phenyl-2-hydroxyethyl]cysteine (PHEC)-induced cytotoxicity in isolated rat renal proximal tubules. The present study has therefore examined in more detail PHEC-induced mitochondrial dysfunction, bothin vivoandin vitro,using isolated renal cortical mitochondria. Renal cortical mitochondria isolated from PHEC-treated ratsin vivoshowed depressed effects on the mitochondrial respiration and oxidative phosphorylation in both a dose (0, 250, and 500 μmol/kg iv)- and time (0–24 h)-dependent manner in the presence of both succinate (Site 2) and malate plus α-ketoglutarate (Site 1) as respiratory substrates, with initial significant depression occurring as early as 4 h following treatment with 500 μmol PHEC/kg. Similar mitochondrial dysfunctions were observedin vitroin concentration- and time-dependent manners with both respiratory substrates. PHEC also caused a marked dose-dependent inhibition of mitochondrial succinate dehydrogenase and NADH cytochromecreductase activities bothin vivoandin vitro,with initial inhibition occurring as early as 4 h afterin vivoadministration and 45 min after exposure to PHECin vitro,while the NADH dehydrogenase activity was not considerably inhibited. The mitochondrial ATPase activity was significantly decreased 4 and 24 h following treatment with PHEC (500 μmol/kg). These results suggest that PHEC exerts its inhibitory effect on the mitochondrial respiration and oxidative phosphorylation through the action on the mitochondrial electron transport chain. PHEC significantly reduced the activity of adenine nucleotide translocase as well as the net uptake of substrates by mitochondria without affecting their efflux within 2–4 h after its injection (500 μmol/kg). On the other hand, significant renal damage, as assessed by morphological study, appeared as early as 24 h following such treatment. The observation of similar effects after bothin vivoandin vitroexposures may suggest that the effect on mitochondria may have a pathogenic role in PHEC-induced renal injury in rats. PHEC produces mitochondrial toxicity that results from an inactivation of mitochondrial anionic substrate transporters as well as from an inhibition of activities of adenine nucleotide translocase and dehydrogenases.